Many bacterial pathogens important to human health evade the immune system by living within white blood cells. Salmonella enterica, a species of gram-negative bacteria that includes the causative agent of human typhoid fever, resides within a class of white blood cells called macrophages. We have demonstrated that in mice, S. enterica subspecies Typhimurium (Salmonella) resides and replicates within hemophagocytic macrophages (HM?s), which are macrophages that have engulfed erythrocytes, platelets, leukocytes and their precursor cells. Our long-term goal is to determine how Salmonella and HM?s interact to cause disease. Mice infected with Salmonella are a natural host-pathogen model system encountered in the wild. Salmonella causes an acute infection in mice that typically resolves into a chronic infection, and the disease course resembles that of typhoid fever. The bacteria colonize the spleen, liver, and the lymph nodes that drain the intestine. We demonstrated the presence of HM?s within the spleen, liver and bone marrow of Salmonella - infected mice and identified HM?s containing Salmonella as late as eight weeks post-infection in the liver, when persistent infection has been established. In Preliminary Studies we developed a flow cytometric assay to identify and separate HM?s from other cell types. This novel methodology along with established approaches enables new exploration of the role of HM?s in disease. The objective of the current proposal is to identify regulatory pathways within HM?s needed to make these cells permissive for Salmonella replication. Completion of the Aims within has potential use in the development of treatments that modulate hemophagocytosis and influence the course of inflammation in infectious and non-infectious circumstances. PUBLIC HEALTH RELEVANCE: The work proposed within has the potential to define new and important mechanisms of host-pathogen interactions not only for Salmonella but by inference for other microbes that trigger HM? accumulation, including Mycobacterium tuberculosis, Leishmania species, and Histoplasma capsulatum. The long-term significance of the proposed research is its potential to identify macrophage signaling pathways as novel therapeutic targets for infectious and non-infectious diseases in which HM?s accumulate.